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Antimicrobial Agents and Chemotherapy, January 2007, p. 89-94, Vol. 51, No. 1
0066-4804/07/$08.00+0     doi:10.1128/AAC.00633-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Multidrug Resistance Conferred by Novel DNA Polymerase Mutations in Human Cytomegalovirus Isolates

Virology Research, POWH and UNSW Research Laboratories,¹ Department of Microbiology, SEALS, Prince of Wales Hospital, Randwick, NSW, Australia,² School of Medical Sciences, Faculty of Medicine,³ School of Biotechnology and Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney, Australia,⁴ Infectious Diseases, Departments of Pediatrics and Medicine, University of Colorado Health Sciences Center, Denver, Colorado,⁵ Medical and Research Services, Veterans Affairs Medical Center, and Division of Infectious Diseases, Oregon Health and Science University, Portland, Oregon⁶

Received 24 May 2006/ Returned for modification 13 July 2006/ Accepted 5 October 2006

The emergence of antiviral-resistant cytomegalovirus (CMV) strains is a continuing clinical problem, with increased numbers of immunocompromised patients given longer-duration antiviral prophylaxis. Two previously unrecognized CMV DNA polymerase mutations (N408K and A834P) identified separately and together in at-risk lung and kidney transplant recipients and a third mutation (L737M) identified in a liver transplant recipient were characterized by marker transfer to antiviral-sensitive laboratory strains AD169 and Towne. Subsequent phenotypic analyses of recombinant strains demonstrated the ability of mutation N408K to confer ganciclovir (GCV) and cidofovir (CDV) resistance and of mutation A834P to confer GCV, foscarnet, and CDV resistance. Mutation L737M did not confer resistance to any of the antiviral agents tested. A recombinant strain containing both N408K and A834P demonstrated increased GCV and CDV resistance compared to the levels of resistance of the virus containing only the A834P mutation. The addition of mutation N408K in combination with A834P also partially reconstituted the replication impairment of recombinant virus containing only A834P. This suggests that perturbation of both DNA polymerization (A834P) and exonuclease (N408K) activities contributes to antiviral resistance and altered replication kinetics in these mutant strains. The identification of these multidrug-resistant CMV strains in at-risk seronegative recipients of organs from seropositive donors suggests that improved prophylactic and treatment strategies are required. The additive effect of multiple mutations on antiviral susceptibility suggests that increasing antiviral-resistant phenotypes can result from different virus-antiviral interactions.

Published ahead of print on 16 October 2006.

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